This case is related to Merck Case 18793IB which is a continuation-in-part of 18793IA, which is a continuation-in-part of Merck Case 18793, filed Aug. 7, 1992, U.S. Ser. No. 07/926,607 now abandoned, and 19345.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is reverse transcription of the RNA genome by a virally encoded reverse transcriptase to generate DNA copies of HIV sequences, a required step in viral replication. It is known that some compounds are reverse transcriptase inhibitors and are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)].
Applicants demonstrate a substantially improved synthesis of an inhibitor of HIV reverse transcriptase, of the structure ##STR1## named (-) 6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxa zin-2-one, hereinafter "Compound A." This compound is highly potent, even against HIV reverse transcriptase resistant to other AIDS antiviral compounds.
Applicants have devised an asymmetric synthesis of Compound A. Prior methods required a racemate penultimate product, with a lower overall yield. The present invention relates to a direct synthesis of the optically active Compound A, by chiral addition to a ketone intermediate to give a tertiary alcohol, with an enantiomeric excess of greater than 95%.
Further, it is unexpected that reaction of an acetylide with a trifluoromethyl ketone produces an optically active product. In the present invention, this is achieved with a chiral amino alcohol to mediate the addition reaction along an asymmetric pathway.
Applicants have also discovered that heating (followed by cooling) the mixture of lithiated chiral amino alcohol and cyclopropylacetylene, before the addition of the trifluoroketone, boosts the enantiomeric excess from about 85% in a typical run to more than about 95%. The unusually high levels of optical activity (&gt;95% ee) make this method advantageous and practical.